A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

Members of the Src family of nonreceptor protein tyrosine kinases (PTKs) ha ve been implicated in the regulation of cellular excitability and synaptic plasticity. We have investigated the role of these PTKs in in vitro models of epileptiform activity. Spontaneous epileptiform discharges were induced in vitro in the CA3 region of rat hippocampal slices by superfusion with th e potassium channel blocker 4-aminopyridine in Mg2+-free medium. In hippoca mpal slices treated in this fashion, Src kinase activity was increased and the frequency of epileptiform discharges could be greatly reduced by inhibi tor of the Src family of PTKs, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazo lo[3.4-d]pyrimidine (PP2), but not by the inactive structural analog 4-amin o-7-phenylpyrazol[3.4-d]pyrimidine (PP3). 4-Amino-5-(4-chlorophenyl)-7-(t-b utyl)pyrazolo[3,4-d]pyrimidine also reduced epileptiform activity induced b y either 4-aminopyridine or Mg2+-free medium alone. These observations demo nstrate a role for Src family PTKs in the pathophysiology of epilepsy and s uggest potential therapeutic targets for antiepileptic therapy.